P876: ANCHOR (OP-104): MELFLUFEN PLUS DEXAMETHASONE AND DARATUMUMAB OR BORTEZOMIB IN RELAPSED/REFRACTORY MULTIPLE MYELOMA—FINAL EFFICACY AND SAFETY RESULTS
Authors: Enrique Maria Ocio San Miguel, Yvonne A. Efebera, Roman Hájek, Jan Straub, Vladimir Maisnar, Jean-Richard Eveillard, Lionel Karlin, Maria-Victoria Mateos, Albert Oriol, Vincent Ribrag, Paul Richardson, Stefan Norin, Jakob Obermüller, Nicolaas A. Bakker, Ludek Pour
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and esterases to rapidly release alkylating agents into tumor cells. Melflufen + dexamethasone (dex) is approved for use in Europe in patients (pts) with triple-class refractory relapsed/refractory multiple myeloma (RRMM) who have received ≥3 prior lines of therapy (LoTs) and progressed >3 y after a prior autologous stem cell transplant if one was received. Approval was supported by the phase 2 HORIZON and phase 3 OCEAN studies (Richardson PG, J Clin Oncol. 2021;39:757-767; Schjesvold F, Lancet Haematol. 2022; 9:e98-e110). Aims: Report the final data for the phase 1/2a ANCHOR study of melflufen with bortezomib + dex (Vd) or daratumumab + dex (Dd) in RRMM (NCT03481556). Methods: Pts must have had RRMM refractory or intolerant to a prior IMiD and/or a proteasome inhibitor (PI) and 1-4 prior LoTs. Vd arm: Prior PI therapy was allowed, but pts could not be refractory to PIs in the last LoT. Dd arm: prior anti-CD38 monoclonal antibody therapy was not allowed. Each 28-day cycle, pts received intravenous (IV) melflufen (30 or 40 mg, day 1). Vd arm: bortezomib 1.3 mg/m2 subcutaneous, days 1, 4, 8, and 11 + oral dex (20 mg on days 1, 4, 8, and 11 and 40 mg on days 15 and 22; dose reduced if aged ≥75 y). Dd arm: daratumumab 16 mg/kg IV once weekly (2 cycles), every 2 wk (4 cycles), then every 4 wk + oral dex (40 mb on days 1, 8, 15, and 22). Primary objectives: determine the optimal melflufen dose in each combination (phase 1); assess overall response rate (ORR; phase 2). Results: As of Feb 9, 2022 (data cutoff date), 23 pts received melflufen (30 mg, n=15; 40 mg, n=8) +Vd and 33 received melflufen (30 mg, n=6; 40 mg, n=27) +Dd (Table). Most pts were refractory to IMiDs; median prior LoTs was higher in the Vd arm but more pts in the Dd arm had been exposed to high-dose alkylators. The partial clinical hold issued by the US Food and Drug Administration led to premature study termination on Feb 23, 2022. Vd arm: Median (range) treatment duration was 8.3 mo (2.8-40.0) in the 30-mg cohort and 12.0 mo (2.1-34.7) in the 40-mg cohort. ORR for the combined cohorts was 78% (2 complete response or better [≥CR], 5 very good partial response [VGPR], 11 partial response [PR]). At a median follow-up of 21 mo, the median progression-free survival (PFS) was 14.7 mo (95% CI, 8.5-33.5); overall survival (OS) was immature with 17 pts (74%) alive at data cutoff. Cytopenias were the most common grade ≥3 treatment-emergent adverse events (TEAEs); thrombocytopenia led to treatment discontinuation in 3 pts; grade ≥3 nonhematologic TEAEs were infrequent. No dose-limiting toxicities (DLTs) and 3 fatal AEs (1 cardiac failure chronic, 2 COVID-19 pneumonia) occurred. Dd arm: Median (range) treatment duration was 24.1 mo (0.9-44.6) in the 30-mg cohort and 6.2 mo (0.9-41.2) in the 40-mg cohort. ORR was 73% (3 ≥CR, 8 VGPR, 13 PR). Median (95% CI) PFS was 12.9 mo (7.7-15.4) and median OS was 26.1 mo (16.4-not estimable), at a median follow-up of 30.0 and 32.8 mo, respectively. Thrombocytopenia and neutropenia were the most common grade ≥3 TEAEs and TEAEs leading to treatment discontinuation; grade ≥3 nonhematologic TEAEs were infrequent. No DLTs and 4 fatal AEs (2 sepsis, 1 cardiac failure chronic, 1 general physical health deterioration) occurred. Summary/Conclusion: Melflufen plus Vd or Dd showed encouraging activity in RRMM with ≥2 prior LoTs. Combined safety and efficacy analyses determined that melflufen 30 mg should be the recommended dose in triplet regimens.Keywords: Bortezomib, Chemotherapy, Multiple myeloma, Clinical data